Abstract
The norepinephrine transporter (NET) has been suggested to play a critical role in attention-deficit/hyperactivity disorder (ADHD). In this prospective controlled study we tested the a-priori-hypothesis that central NET availability is altered in adult ADHD patients compared to healthy controls. Study participants underwent single positron emission tomography-magnetic resonance imaging (PET-MRI). MRI sequences included high resolution T1-MPRAGE data for regions of interest (ROI) delineation and voxel-based morphometry (VBM) and T2-weighted fluid-attenuated inversion-recovery for detection and exclusion of pathological abnormalities. NET availability was assessed by NET-selective (S,S)-O-[11C]methylreboxetine; regional distribution volume ratios (DVR) were calculated based on individual PET-MRI data co-registration and a multi-linear reference tissue model with two constraints (MRTM2; reference region: occipital cortex). VBM analysis revealed no difference in local distribution of gray matter between the 20 ADHD patients (9 females, age 31.8 ± 7.9 years, 488 ± 8 MBq injected activity) and the 20 age-matched and sex-matched control participants (9 females, age 32.3 ± 7.9 years, 472 ± 72 MBq). In mixed-model repeated-measures analysis with NET availability as dependent and ROI as repeated measure we found a significant main effect group in fronto-parietal-thalamic-cerebellar regions (regions on the right: F1,25 = 12.30, p = .002; regions on the left: F1,41 = 6.80, p = .013) indicating a reduced NET availability in ADHD patients. None of the other investigated brain regions yielded significant differences in NET availability between groups after applying a Benjamini-Hochberg correction at a significance level of 0.05. Overall our findings demonstrate the pathophysiological involvement of NET availability in adult ADHD.
Highlights
Adult attention-deficit/hyperactivity disorder (ADHD)is an underrecognized chronic disorder with childhood-a mortality rate of 5.8% has been found in ADHD, highest in individuals diagnosed in adulthood and mainly driven by deaths from unnatural causes, e.g., accidents[3]
We further explored whether norepinephrine transporter (NET) availability is associated with ADHD symptom severity, neuropsychological and neurophysiological measures
Description of sample The final study sample consisted of 20 adult patients with ADHD (11 males, age 31.8 ± 7.9 years, 488 ± 8 MBq injected activity) and 20 age- and sex-matched healthy controls (11 males, age 32.3 ± 7.9 years, 472 ± 72 MBq)
Summary
Adult attention-deficit/hyperactivity disorder (ADHD)is an underrecognized chronic disorder with childhood-a mortality rate of 5.8% has been found in ADHD, highest in individuals diagnosed in adulthood and mainly driven by deaths from unnatural causes, e.g., accidents[3]. The economic impact of adult ADHD places a significant burden on society. The gold standard treatment is pharmacotherapy, but 30% of adult patients with ADHD do not respond to medication[6,7]. Patients with ADHD show executive functioning deficits, impaired attention and behavioral control, relating to brain areas modulated by noradrenergic transmission[8,9] and norepinephrine transporter (NET) expression. Animal models of ADHD demonstrate the involvement of the central locus-coeruleus norepinephrine (LC-NE) system in behavioral control and the attentive process[10,11]. Drugs modulating NE transmission and targeting NET, such as atomoxetine or methylphenidate, are effective in ADHD patients[6] and have been shown to significantly occupy NET in vivo at clinically relevant doses[12,13]. There is ample and clear evidence that the LC-NE system is involved in regulating wakefulness and arousal[14,15] shown to be reduced in patients with adult ADHD16–18
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